GCIG Cervix Committee: Sunday, November 17, 2013, 10:30 a.m. – 12:00 noon
Room 2+3, UCL Education Centre, London, UK.
Satoru Sagae (JGOG)
Bradley Monk (GOG)
Bill Small (RTOG) President elect
Publications:
M McCormack, et al. A phase II study of weekly neoadjuvant chemotherapy followed by Radical chemoradiation for locally advanced cervical cancer
Br J Cancer (2013) 108, 2464–2469
Closed studies:
GOG 240 (MANGO, NSGO): Cis/Paclitaxel +/- Bev vs Topo/Paclitaxel +/- Bev
in stage IVB cervix cancer (Tewari) Presented at ASCO 2013 plenary
ACRIN 6671(GOG, KGOG, JGOG) Utility of Preoperative FDG-PET/CT
Prior to Primary Chemoradiation Therapy to Detect Retroperitoneal Lymph Node
Metastasis in Patients With advanced cervical and endometrial Carcinoma
CURRENT ACTIVE/NEAR ACTIVATION RANDOMIZED TRIALS
WITH GCIG PARTICIPATION:
KGOG-Thai TACO: (RTOG, GICOM) (CCRN - Viet Nam, Thailand)
Randomized Clinical Trial of Weekly versus Tri-Weekly Cisplatin based
Chemoradiation in Locally Advanced Cervical Cancer Ryu 75/590
ANZGOG OUTBACK (GOG, RTOG) (CCRN - India) : Chemoradiotherapy +/-
adjuvant chemotherapy Mileshkin 254/780
NCRI: INTERLACE:(CCRN – Romania, Belarus) INduction ChemoThERapy in Locally Advanced CErvical Cancer. McCormack 14/700
NCIC-CTG CX 5 SHAPE: (DGOG, ) (CCRN -- ) A RANDOMIZED TRIAL
COMPARING RADICAL HYSTERECTOMY AND PELVIC NODE DISSECTION
VS SIMPLE HYSTERECTOMY AND PELVIC NODE DISSECTION IN PATIENTS
WITH LOW RISK EARLY STAGE CX CA: Plante 11/700
GOG-0278 Conservative surgery (cone/nodes or hyst/(nodes) in early stage cervical cancer. (evaluation of physical function and QOL) Monk 9/220
GOG-0279 Phase II Trial Evaluating Cisplatin (NSC #119875) and Gemcitabine (NSC #613327) Concurrent with Intensity-Modulated Radiation Therapy (IMRT)
in Treatment of Locally Adv. SCC of the Vulva Monk 9/52
KGOG-0801/GOG 263 (RTOG): RT vs CRT in intermediate risk cervix cancer
after hysterectomy Ryu 145/480
RTOG-0724 (GOG): ChemoRT with and without adjuvant chemotherapy in high risk cervix cancer after hysterectomy Small <100/400
RTOG: A RANDOMIZED PHASE III STUDY OF STANDARD VS. IMRT PELVIC
RADIATION FOR POST-OPERATIVE TREATMENT OF ENDOMETRIAL AND CERVICAL CANCER: TIME-C Small too early/284
DGOG GROINSS-V II (EORTC, GOG) : Groningen International Study on Sentinel
Nodes in Vulvar Cancer Creutzberg for van der Zee 1,037 cases
EORTC 55994: Randomized phase III study of NAC followed by RH vs CCRT in FIGO stage Ib2, IIa>4 cm or IIb cervical cancer Casado 594/625
PROPOSED OR DEVELOPING CONCEPTS:
JGOG1074;A New Protocol Concept for Advanced Cervical Adenocarcinoma of the
Uterine Cervix CCRT-P (RT + CDDP 40 mg/m2 weekly) VS CCRT-TP (RT + CD
DP 30 mg/m2 + PTX 50 mg/m2 weekly) Fujiwara 240
TACO (Tri-weekly Administration of Cisplatin in LOcally Advanced
Cervical Cancer)
Cervical cancer Locally advanced cervical cancer Stage IB2, IIB-IVA
Control Arm; Weekly Cisplatin 40mg/m2 6 cycles
Study Arm; Tri-weekly Cisplatin 75mg/m2 3 cycles
Random
ization
RT-QA
• 3th RT-Film review at Seoul 2013.10
RPC Contract
• Radiological Physics Center’s Justification for staff needed to
perform the radiotherapy quality assurance
IDMC
• IDMC meeting in GCIG(London 2013. 11)
• Status of study; enrollment, safety
OUTBACK A Phase III trial of adjuvant
chemotherapy following chemoradiation as
primary treatment for locally advanced cervical
cancer compared to chemoradiation alone
Study Chair: Linda
Mileshkin Study Coordinator: Ilka
Kolodziej
Current status • 140 Sites open
– 12 sites in Australia – 3 sites in New Zealand – 121 sites in the USA – 3 sites in Canada – 1 site in Saudi Arabia
• 254 Patients recruited
– 58 patients from Australia – 9 patients from New Zealand – 185 patients from the USA – 2 patients from Saudi Arabia
• First interim analysis completed and approved by IDSMC
• 23 QA reports finalized - 5 major deviations - 13 minor deviations • Ongoing high rate of SAEs during
chemoRT - no SUSARS
Next steps
• Complete site activations in USA & Canada • Start trial in Singapore (has now passed RTOG audit) • Discuss proposal by Dutch Oncology Group to join with
specific amendment to allow only them to use IMRT (9 centres)
- need local arrangement for QA of their RT
INduction ChemoThERapy in Locally Advanced CErvical Cancer
INTERLACE
Chief Investigator: Mary McCormack GCIG Meeting – London
17th November 2013
INTERLACE
Randomise
Carboplatin AUC2 & Paclitaxel 80mg/m2
Weeks 1-6
Weeks 7 – 13 Standard CRT
Standard CRT
Follow-up 3 monthly for 2 years; 6 monthly for 3 years
Standard CRT : 40—50.4Gy in 20-28 fractions plus Intracavitary brachytherapy to give total EQD2 dose of 78-86Gy to point A/volume. Weekly cisplatin 40mg/m2 x 5 weeks
Current Status – UK & International • Target accrual – 770 patients • Open to UK recruitment – September 2012 • 5 UK Sites open • 14 patients recruited • 40 UK Sites in set-up – RTQA cause for delay • International:
• Mexico in set-up (2 sites)
• Eire in set-up (7 sites)
• TOTAL = 54 Sites
A RANDOMIZED TRIAL COMPARING RADICAL HYSTERECTOMY AND PELVIC NODE DISSECTION VS SIMPLE HYSTERECTOMY AND PELVIC NODE DISSECTION
IN PATIENTS WITH LOW RISK EARLY STAGE CERVICAL CANCER
A Gynecologic Cancer Intergroup (GCIG) Trial led by the NCIC CTG
GCIG Trial Designation: The SHAPE Trial NCIC CTG Protocol Number: CX.5
Chair: Marie Plante
SHAPE-UPDATE Centers opened in Canada: 13 Accrual to date: 11 International groups status
The Netherlands have received approval and funding ! UK Group has received approval for funding and will be opened to accrual by
Spring 2014 Austria has received approval and will activate by the end of 2013. France and Germany will activate by Spring 2014. Ireland will activate by the end of 2013. The Nordic Society will activate by the end of 2013. The Belgium Group will activate by the end of 2013. Mexico, Korea, China and COGI (the group at Stanford Uni): ???
SHAPE-UPDATE
Adjuvant treatment Will be left at the discretion of each center based on local policy Specific references to Cisplatin administration has been
removed from the protocol This amendment has been submitted to Health Canada
(October 2013) Simplified randomization process
Maximum of 20 weeks from diagnosis The surgical approach is no longer a stratification factor All patients must undergo PLND
SLN optional LSG optional (preferred)
Gynecologic Oncology Group
Bradley J. Monk, MD, FACS, FACOG Chair GOG Cervical Cancer Committee
Professor and Director Division of Gynecologic Oncology
St. Joseph’s Hospital and Medical Center, a Dignity Health Member Phoenix, Arizona USA
Gynecologic Oncology Group
Current GCIG Studies in the GOG
1. GOG 263 (KGOG) 2. GOG 0724 (RTOG) 3. GOG 0274 (ANZGOG) 4. GOG 233 (ACRIN) 5. TIME-C (RTOG) 6. GOG 270 (GROINSS-V II)
GOG 263/KGOG 1008 PI; Sang Young Ryu, MD
Randomized Phase III Clinical Trial of Adjuvant Radiation vs Chemoradiation In Intermediate
Risk, Stage I/IIA Cervical Cancer Treated With Initial Radical Hysterectomy and Pelvic Lymphadenectomy
Cervical cancer Stage I-IIA Radical hysterectomy+BPLND >2 of intermediate risk factors
Control Arm; Radiation therapy
CRT Arm; Weekly CDDP 40mg/m2
concurrent to radiation R
andomization
Accrual of GOG 263
0
50
100
150
10-1
0 10
-11
10-1
2 11
-1
11-2
11
-3
11-4
11
-5
11-6
11
-7
11-8
11
-9
11-1
0 11
-11
11-1
2 12
-1
12-2
12
-3
12-4
12
-5
12-6
12
-7
12-8
12
-9
12-1
0 12
-11
12-1
2 13
-1
13-2
13
-3
13-4
13
-5
13-6
13
-7
13-8
13
-9
13-1
0 13
-11
Golobal
Golobal
25
INCORPORATION OF BEVACIZUMAB IN THE TREATMENT OF RECURRENT AND METASTATIC
CERVICAL CANCER
GOG 240: A PHASE 3 RANDOMIZED TRIAL OF THE GYNECOLOGIC ONCOLOGY GROUP
KS Tewari, MW Sill, HJ Long 3rd, RT Penson, LM Ramondetta, LM Landrum, A Oaknin, TJ Reid,
MM Leitao, HE Michael, BJ Monk
26
GOG 240: Schema
KS Tewari (study chair). www.ClinicalTrials.gov Identifier: NCT00803062.
Activated: 4/6/09 Closed to accrual: 1/3/12
R A N D O M I Z E
Presented by: Krishnansu S. Tewari, MD, FACOG, FACS
Carcinoma of the cervix •Primary stage IVB •Recurrent/persistent •Measureable disease •GOG PS 0–1 •No prior chemotherapy for recurrence
(N=452)
Stratification factors: •Stage IVB vs recurrent/persistent disease •Performance status •Prior cisplatin Rx as radiation-sensitizer
1:1:1:1
I Paclitaxel 135 or 175 mg/m2 IV
Cisplatin 50 mg/m2 IV
III Paclitaxel 175 mg/m2 IV
Topotecan 0.75 mg/m2 d1-3
Chemo alone
II Paclitaxel 135 or 175 mg/m2 IV
Cisplatin 50 mg/m2 IV
Bevacizumab 15 mg/kg IV
IV Paclitaxel 175 mg/m2 IV
Topotecan 0.75 mg/m2 d1-3
Bevacizumab 15 mg/kg IV
Q21d Rx to PD, toxicity, CR
Chemo + Bev
27
GOG 240: Objectives • Primary end points to determine
– If adding bevacizumab to chemotherapy improves OS – If a non-platinum doublet (topotecan + paclitaxel) improves OS – The tolerability of the four regimens (adverse events by CTCAE v3 and v4)
• Secondary end points to determine – Impact of bevacizumab and non-platinum doublet on progression-free survival (PFS) and
overall response rate (ORR) by RECIST v1.0 • Exploratory end points
– Impact on Health-Related Quality of Life (HRQoL): • Functional Assessment of Cancer Therapy – Cervix Ca Trial Outcome Index (FACT-Cx TOI)
– Data not included in current presentation • Additional HRQoL: FACT/GOG-Ntx (neuropathy), BPI (Brief Pain Inventory) • Prospective validation of pooled clinical prognostic factors from prior phase 3 trials • Prevalence and impact of nicotine dependence on OS and PFS • Circulating tumor cells and VEGF isoform expression
KS Tewari (study chair). www.ClinicalTrials.gov Identifier: NCT00803062.
Presented by: Krishnansu S. Tewari, MD, FACOG, FACS
28
Characteristic Chemo Alone
(n=225), % Chemo + Bev
(n=227), % Median age, years (range) 46 (20–83) 48 (22–85)
Histology, % Squamous AdenoCa, unspec.
68 20
70 19
Race, % White African American Asian Pacific Islander
80 11 3 0
75 16 5 0
Stage of disease, % Recurrent Persistent Advanced
73 10 16
70 12 17
Performance status, % 0 1
58 42
58 42
Prior platinum, % 74 75
Pelvic disease, % 53 54
GOG 240: Demographics & Baseline Characteristics
Presented by: Krishnansu S. Tewari, MD, FACOG, FACS
29
Chemotherapy (n=225)
Events, n (%) 140 (62)
Median OS, mos 13.3
Chemotherapy + Bev (n=227)
131 (58)
17.0
HR=0.71 (97% CI, 0.54-0.94) P=0.0035
GOG 240: OS for Chemo vs Chemo + Bev
Presented by: Krishnansu S. Tewari, MD, FACOG, FACS
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
0 12 36 24
Pro
porti
on S
urvi
ving
Months on Study
Median follow-up 20.8 mos
30
Chemotherapy + Bev (n=227)
183 (81)
8.2
HR=0.67 (95% CI, 0.54-0.82) 2-sided P=0.0002
GOG 240: PFS for Chemo vs Chemo + Bev
Presented by: Krishnansu S. Tewari, MD, FACOG, FACS
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
0 36 12 24
Pro
porti
on P
rogr
essi
on-F
ree
Months on Study
Chemotherapy (n=225)
Events, n (%) 184 (82)
Median PFS, mos 5.9
RR, % 36 (CR, n=14) 48 (CR, n=28) 2-sided P=0.00807
31
Cis + Pac + Bev (n=115) 67 (58.3)
17.5
HR=0.68 (95% CI, 0.48-0.97) P=0.0348
Cis + Pac (n=114)
Events, n (%) 69 (60.5)
Median OS, mos 14.3
GOG 240: OS for Cisplatin + Paclitaxel vs Cisplatin + Pac + Bev
Presented by: Krishnansu S. Tewari, MD, FACOG, FACS
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
0 12 36 24
Pro
porti
on S
urvi
ving
Months on Study
RR, % 45 (CR, n=9) 50 (CR, n=17) 2-sided P=0.5090
32
GOG 240: Treatment Exposure and Specific Adverse Events Adverse Event, n (%) Chemo Alone
(n=219) Chemo + Bev
(n=220)
Treatment cycles, median (range) 6 (0-30) 7 (0-36)
Grade 5 AE(s) 4 (1.8) 4 (1.8)
GI events, non-fistula (grade ≥2) 96 (44) 114 (52)
GI fistula (grade ≥3)* 0 (0) 7 (3)
GI perforation (grade ≥3) 0 (0) 5 (2)
GU fistula (grade ≥3)* 1 (0) 6 (2)
Hypertension (grade ≥2)* 4 (2) 54 (25)
Proteinuria (grade ≥3) 0 (0) 4 (2)
Pain (grade ≥2) 62 (28) 71 (32)
Neutropenia (grade ≥4)* 57 (26) 78 (35)
Febrile neutropenia (grade >3) 12 (5) 12 (5)
Thromboembolism (grade ≥3)* 3 (1) 18 (8)
Bleeding CNS (any grade) 0 (0) 0 (0)
GI (grade ≥3) 1 (0) 4 (1)
GU (grade ≥3) 1 (0) 6 (3)
Presented by: Krishnansu S. Tewari, MD, FACOG, FACS
*p<0.05
33
• Bevacizumab plus chemotherapy significantly improves OS in stage IVB, recurrent or persistent cervical carcinoma – Nearly 4-month improvement in OS is clinically significant – Increase in median PFS and ORR are also demonstrated – Cisplatin + paclitaxel arm is current standard of care and did not
underperform – Benefit seen even when recurrent disease is in irradiated pelvis
• Bevacizumab treatment is associated with a higher rate of AEs – 3–8% rate of known bevacizumab-related AEs
• The improvement in OS with bevacizumab treatment was not accompanied by a decrease in HRQoL
• First targeted agent to improve OS in a gynecologic cancer
GOG 240: Conclusions
Presented by: Krishnansu S. Tewari, MD, FACOG, FACS
RTOG-0724 (GOG): ChemoRT with and without
adjuvant chemotherapy in high risk cervix cancer after hysterectomy
Schema STRATIF Y Intention To Use Brachytherapy: No Yes
RT Modality: 3D-CRT IMRT
RANDOMIZE Concurrent weekly cisplatin plus 50.4 Gy tailored RT ± brachytherapy
Versus
Concurrent weekly cisplatin plus 50.4 Gy tailored RT ± brachytherapy
followed by 4 courses of carboplatin and paclitaxel
Arms/Regimens Arm 1: Concurrent weekly cisplatin 40 mg/m2 plus 50.4 Gy tailored RT ± brachytherapy
Arm 2: Concurrent weekly cisplatin 40 mg/m2 plus 50.4 Gy tailored RT
± brachytherapy followed by paclitaxel 175 mg/m2 and carboplatin AUC of 5
every 21 days for 4 cycles
C O - P I S A N N K L O P P M D , P H D
A N A M A R I A Y E U N G M D
P R O A N D Q O L C O - C H A I R L A R I W E N Z E L , P H . D .
K A R E N G I L , P H . D .
C O S T A N A L Y S I S C O - C H A I R A N D R E K O N S K I , M D , M B A , M A , F A C R
S T A T I S T I C I A N
S T E P H A N I E S H O O K
A RANDOMIZED PHASE III STUDY OF STANDARD VS. IMRT PELVIC RADIATION FOR POST-
OPERATIVE TREATMENT OF ENDOMETRIAL AND CERVICAL CANCER (TIME-C)
P
P
P P
Eligibility Women with
endometrial or cervical cancer requiring post-operative pelvic
radiation or chemoradiation
RANDOMIZE
IMRT pelvic radiation treatment
4-field pelvic radiation treatment
P
Stratification factors XRT dose
• 45 Gy • 50.4 Gy
Chemotherapy • No Chemotherapy • 5 cycles of weekly
cisplatin at 40mg/m2
Disease Site •Endometrial
•Cervix
Schema
Accrual GROINSS-V-II: December 2005 – October 2013
(n = 1037)
0
200
400
600
800
1000
1200
Cumulative inclusion 3-monthly
Mean = 32 inclusions / 3 months
After protocol amendment: 41 – 68 inclusions / 3 months !
GROINSS-V-II 777 patients data SN available: • 600 negative SN (77%)
• 177 positive SN (23%)
– Micrometastases (</= 2mm) 85 (48%) – Macrometastases (> 2mm) 79 (45%) – 13 missing (7%)
• Pts with macrometastases now undergo inguinofemoral lymphadenectomy
• Until now safety border for SN+/micro (treated with radiotherapy) not crossed
• Final inclusion expected: end 2015 • Results expected: end 2017
Arm 1: Neoadjuvant QT Cisplatin based chemotherapy : -min. cumulative cisplatin dose of 225 mg/m2
-25 mg/m2 per week, -final dose no later than D64 Followed by surgery (radical hysterectomy)
Arm 2: concomitantly QT/RDT Cumulative cisplatin dose 200-240 mg/m². - Max 6 administrations. - Dose 40 mg/m2, max 80 mg External radiotherapy (45-50 Gy) in fractions of 1.8 Gy to 2 Gy + external boost or brachytherapy - min. 75 Gy EQD2 to point A (80 Gy to High Risk PTV) is mandatory - overall treatment time ≤ 50 days
Cervix Cancer. Treatment Scheme
Eligibility Check
Randomization EORTC 55994
PIs: G. Kenter, S. Greggi, F. Landoni
N=686
EORTC 55994. Current status • Activation of new sites ongoing • Recruitment (November 8th 2013): 594 patients
• Given the slow accrual and the very long-term follow-
up needed to accumulate the required number of events both for OS and PFS, the required number of events will not be reached within a reasonable timeframe.
EORTC 55994. Current status
• The recommendation was then to redesign the trial with a binary endpoint.
• The first choice was OS rate at 5 years which was the initial objective of the trial.
• Under a 10% difference in OS rate at 5 years OS rate at 5 years of 67% in the control arm OS rate at 5 years of 77% in the experimental arm Sample size required (two sided type I error of 5% and
power of 80%): 625 patients
A New Protocol Concept for Advanced Cervical Adenocarcinoma of
the Uterine Cervix
Department of Obstetrics and Gynecology,
Graduate School of Medical Science,
University of the Ryukyus,
Okinawa, JAPAN
Yutaka Nagai, M.D., Ph.D.
Prospective trials in larger series of patients undergoing CCRT with PTX and CDDP (CCRT-TP) are urgently needed for local advanced cervical adenocarcinoma.
“ Proposal for a new clinical trial ”
Primary endpoint: 5-yr OS
Secondary endpoints: 5-yr PFS, 5-yr local PFS, 5-yr distant PFS, completion rate, and adverse events
R A N D O M I Z A T I O N
Cervical Cancer, FIGO IIIA, IIIB, IVA adenocarcinoma, and adenosquamous carcinoma age; 20 – 70, PS; 0-1, and no PAN enlargement
CCRT-P Radiotherapy + CDDP 40 mg/m2 weekly
CCRT-TP Radiotherapy + CDDP 30 mg/m2 weekly PTX 50 mg/m2 weekly
Control Arm
Experimental Arm